Lupus, a multigenic autoimmune condition in which a breakdown of tolerance results in the development of autoantibodies, leads to a variety of pathologic outcomes. Despite the heterogeneity of factors influencing disease susceptibility, we demonstrate that the partial restoration of inhibitory Fc receptor (FcγRIIB) levels on B cells in lupus-prone mouse strains is sufficient to restore tolerance and prevent autoimmunity. FcγRIIB regulates a common B cell checkpoint in genetically diverse lupus-prone mouse strains, and modest changes in its expression can result in either tolerance or autoimmunity. Therefore, increasing FcγRIIB levels on B cells may be an effective way to treat autoimmune diseases.
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